Calcium lactulosate

ABSTRACT

Calcium lactulosate prepared by introducing into a dilute aqueous solution of a crude lactulose syrup about 0.7 to 4 parts by weight of calcium oxide per part by weight of lactulose in the crude syrup at a temperature of about 0* to 15* C., allowing the resultant mixture to stand under conditions permitting maintenance of the temperature to about 0* to 15* C., and separating off the calcium lactulosate thereby formed.

United States Patent Field oi Search ....260/209 Reinicke et al. [451Sept. 19, 1972 CALCIUM LACTULOSATE 72 Inventors: Hans Reinicke,Schwarzwaldstrasse [561 CM 56; Seats Leonhauser, Kallstader Strasse 11,both of, 6804 Ilvesheim UNITED STATES PATENTS Bei Mannheim; Rudolf3,505,309 4/1970 Carubelli ..'...260/209 R Weidenhagen, EmsheimerStrasse 3,546,206 12/1970 Guth et a1. .;.....260/209 R 40, 6501Ulversheim Uber Mainz, all of Germany Primary Examiner--Lewis' Gotts 22]Filed: Oct 22 19 0 Assistant Examiner-J0hnnie R. Brown Attorney-Burgess,Dinklage & Sprung [21] Appl. No.: 83,161

Related us. Application Data [57] ABSTRACT [62] Division of Ser. NO.773,671, Nov. 5, 1968, P by immducing a Pat 3 562012. dilute aqueoussolution of a crude lactulose syrup about 0.7 to 4 parts by weight ofcalcium oxide per 30 Fore A cation Prion Data part by weight oflactulose in the crude syrup at a tem- 1 an p ty perature of about 0 to15 (3., allowing the resultant 1967 43 834-9 mixture to stand underconditions permitting maintenance of the temperature to about 0 to 15C., and USI Cl- R, eparating ofi the cal ium lactulosate thereby formed[51] Int. Cl ..C07c47/l8 1 Claim, No Drawings CALCIUM LACTULOSATE Thiscase is a division of application, Ser. No. 773,671, filed Nov. 5, 1968and now U.S. Pat. No. 3,562,012.

The invention relates to a process for recovering lactulose from crudesyrups containing it, and more particularly relates to a process forpreparing pure lactulose from crude lactulose syrup.

Lactulose is a disaccharide which has the structure of a4-o-B-D-galactopyranosyl-D-fructose. Conventionally lactulose isprepared from lactose by epimerization with lime or with basic ionexchangers. The crude lactulose syrups thus obtained are mixtures ofdifferent sugars, and predominantly of lactulose, lactose and galactose.

Lactulose has recently taken on considerable medical interest, as it hasbeen found to possess a bifidogenous action, that is, a Bifidus floracan be produced in the intestine following the administration oflactulose. This Bifidus flora prevents the formationof toxic substancesin the intestine, which can, in turn, lead to hepatic encephalopathy,this being particularly true in connection with pathological liverailments. A laxative effect is also ascribed to lactulose.

The use of lactulose in either of the above clinically in- 1 dicatedareas has hitherto been restricted by the fact that the production ofpure lactulose from crude lactulose syrups has been extremely difficult.

According to one known process, lactose is first removed as far as ispossible by crystallization and the remaining lactulose containing syrupoxidized anodically in the presence of sodium bromide or directly withbromine. The acids or salts which are formed as by-products in thisreaction are then removed via ion exchangers and the relatively purelactulose thereafter obtained from the eluate. Purification by thismethod involves numerous steps, and, because of these steps includingthe oxidation with bromine or the electrolytic oxidation, the ionexchange treatment and the fractional crystallization, it is expensiveand very difficult to carry out on a large technical scale.

it is an object of this invention to provide a commercially feasiblemethod for the preparation of satisfactorily pure lactulose.

It is a further object of this invention to provide a method which maybe utilized in the commercial production of lactulose in highly purifiedform with a savings in time, labor and equipment costs.

Other objects and various further features of the present invention willbecome apparent from the following description.

In accordance with the invention it has now been discovered thatlactulose can, under certain conditions, be separated from sugarsaccompanying the same in the form of a difficulty soluble calciumhydroxide compound. The discovery that a difficulty soluble calciumcompound of lactulose could be prepared is to be considered verysurprising, because the formation of such a compound has never beenobserved in the known lime epimerization process.

This product shall be referred to hereinafter as calcium lactulosate,although its chemical composition has not yet been precisely determined.

The process according to the invention for the preparation of purelactulose from crude lactulose syrups comprises introducing into adilute aqueous crude lactulose solution approximately 0.7 to 4 parts byweight of calcium oxide per part by weight of lactulose in the crudesyrup at a temperature of O-l 5 and preferably 5-l0 C., allowing theresulting mixture to stand for a time while maintaining thistemperature,

separating the calcium lactulosate formed while maintaining the sametemperature, washing the calcium lactulosate thoroughly with cold water,resuspending it in water at 0l5 C., freeing the lactulose from its saltby separating the calcium by conventional methods and preferably by theprecipitation of a difficulty soluble calcium salt, and recovering thepure lactulose by concentrating the solution thus obtained.

The freeing of the lactulose from the calcium lactulosate is carried outin a particularly simple and advantageous manner by introducing gasescontaining C05 and filtering out or centrifuging off the precipitatedcalcium carbonate.

Almost any crude syrup containing lactulose is suitable for use in theprocess of the invention. The lactulose syrups which are obtained by theepimerization' of lactose can be used. These can also be obtainedcommercially. In carrying out the calcium precipitation of the lactuloseit is important that not too much lactose and galactose be present inthe starting solution. When the starting crude lactulose syrups have ahigh lactose content, it is advantageous to first separate the lactoseinsofar as is possible by crystallization, using the known methods forthis purpose.

It has been found in accordance with the invention that the best yieldsof lactulose are obtained by the calcium hydroxide precipitation whenthe ratio of lactulose to lactose to galactose amounts to l:0.2:0.l7 inparts by weight. In other words, the yield and purity of productobtained by the calcium precipitation of lactulose is just as good whenas many as 20 parts of lactose and as many as 17 parts of galactose aresimultaneously present per 100 parts of lactulose as when starting fromsyrups containing essentially only lactulose. When the lactose and/orgalactose content rises above the permissible level up to about twicethe above indicated quantities, the yield of the desired calcium saltprecipitated out gradually diminishes.

When the lactose concentration is higher than that stated above, thereduction in yield can be compensated by increasing the amount ofcalcium oxide used, the amount .of calcium oxide having to be increasedby approximately the same part by weight as the amount of lactose in thecrude syrup difiers from the permissible value. Alternatively thequantity of lactose present in the syrup may be reduced in weight by a'removal of at least part of the lactose by crystallization.

When the quantity of galactose in the mixture is substantially above thepermissible value, it must be reduced and preferably before theprecipitation with the calcium oxide is effected.

Crude epimerization syrups usually contain about percent solids, whichin turn have a lactulose content of 50 to 60 percent. parts of crudesyrup therefore contain about 35 to 42 parts of lactulose. According tothe process of the invention, 30 to 37 parts of lactulose can berecovered from such syrups having an [a]D* of 42, and from this about 28to 34 parts of pure lactulose having an lalD of 49, can be recovered, ifdesired, by recrystallization from methanol.

It is advantageous to dilute the commercial crude syrup with water toproduce a solids concentration (Brix) of 70-2, preferably 20-10 Brix,prior to the calcium hydroxide precipitation. In order to precipitatethe calcium lactulosate, calcium oxide is added in a sufficient quantityto the dilute lactulose syrup. Preferably the calcium oxide is added inan amount approximately equal to the lactulose content in the crudesyrup,

' although it is also possible to use smaller quantities of calciumoxide, i.e., amounts down to about 0.7 parts of calcium oxide per partof lactulose. It isadvantageous to increase the amount of calcium oxideabove the 1:1 weight ratio when the ratio of lactulose to lactose in thestarting syrup differs from the optimum range as specified hereinbefore.

The calcium oxide is added preferably in the form of a homogeneous milkof lime.

When the milk of lime is added, care must be taken to maintain thetemperature range of --1 preferably 5-l0 C. constant. The rate ofaddition of the milk of lime, the intensity of the stirring and theamount of cooling are dependent upon the requirement for maintaining thestated temperature.

After the addition of the milk of lime the suspension is allowed tostand for a short period of time in the above temperature range. Thestanding time should amount to about h an hour to 2 hours, depending onthe temperature which is being maintained. Preferably the suspension isallowed to stand for about an hour at a temperature of 5-l0 C. In thisperiod a certain aging of the calcium lactulosate takes place, whichfacilitates the separation which later takes place. Thereafter theprecipitated calcium lactulosate is separated from the liquid phase byany conventional acceptable method and preferably it is separated bycentrifuging or suction filtering. The separated calcium lactulosate isthoroughly washed with cold water, preferably ice water. Most preferablythe washing is continued until the substance is substantially white.

The lactulose is then freed from the calcium lactulosate by separationof the calcium by conventional methods, preferably by dissociation ofthe salt with an acid that forms a difficulty soluble calcium salt withthe calcium. Carbon dioxide is preferably used, because it is verycheap, forms an easily separable precipitate, and introduces no foreignmaterials into the solution. The precipitation of the calcium withoxalic acid, as the calcium oxalate formed is also easy to separate offis also a preferred method.

ln-the calcium separation process, the temperature is to be kept withinthe stated range for as long as the pH value is still relativelystrongly alkaline.

As soon as the pH approaches neutrality, the cooling can bediscontinued. If the dissociation of the calcium salt of the lactuloseis carried out by the introduction of gases containing carbon dioxide,the introduction of gas is discontinued when the pH of the mixtureamounts to between 7.5 and 6.7. Too low a pH must be avoided because ofthe danger of the formation of bicarbonate as a result of which calciumions would be kept in solution.

The precipitated, difficulty soluble calcium salt is dried.

The concentration of the filtrate is preferably carried out in vacuowith heating. Excessively high temperatures are to be avoided thereby asa discoloration of the product will occur.

After the complete evaporation of the filtrate remaining following theremoval of the calcium salt, the residue remaining is lactulose in asolid, very pure state, having a rotation [a]D of about 42. The yieldamounts to about 30 to 35 parts per 100 parts of crude syrup having aninitial content of 35 to 40 parts of lactulose. The recyrstallization ofthis lactulose from methanol increases the rotation [a]D to about --49.5The yield of this pure crystallized product then amounts to about 28 to30 parts.

It is advantageous to extract any galactose present from the filtrateobtained in the production of the calcium lactulosate.

The process of the invention is distinguished particularly by itsextraordinary simplicity. It can be carried out without expensiveapparatus, using no other reagents than calcium oxide, CO and water. Dueto its simplicity it is particularly well suited for'the production ofpure lactulose on a large technical scale, and in this it is very muchsuperior to the purification processes known hitherto.

The following Example illustrates the present invention which is not tobe considered as limited thereby.

EXAMPLE 100 parts by weight of crude lactulose syrup were diluted with500 parts by weight of water and then cooled to about 5 to 10 C. 35parts by weight of calcium oxide were slaked with 350 parts by weight ofwater so as to produce a uniform, grit-freemilk of lime. Any coarseparticles present were separated off by filtering. The milk of lime wasthen also cooled to from 5 to 10 C.

The milk of lime thereby obtained was then very rapidly poured into thedilute lactulose syrup under strong agitation and good cooling, thetemperature not being allowed to rise above 15 C. This resulted in theformation of a mass which gradually became jelly-like, becomingincreasingly thicker upon one hour of standing in the cold state. Aneasily filterable calcium lactulosate suspension formed, which wassuction filtered through a refrigerated Buchner funnel. Thisdoublewalled Buchner funnel was cooled down to about 2 C.

The filter cake was washed with a total of about 700 parts by weight ofice water in portions of 100 parts each. The washed filter cake wastransferred to a vessel that had been previously chilled to theabove-stated temperature range, and was therein suspended in water to afinal volume of about 800 parts by weight, with stirring. During thistime, care was taken to ensure that the temperature did not rise above10 C.

Carbondioxide was then introduced into the suspension until a pH valueof about 7.0 had been reached, under continued refrigeration of thesuspension. The

calcium carbonate was allowed to settle out and was then separated offby filtering. The cooling was discontinued as soon as the pH value of 7had been reached.

The filtrate which was thereby obtained was dried in a rotatoryevaporator, the water bath temperature thereof being maintained at about60 to As it is advantageous to remove the last traces of water from theconcentrate an azeotropic distillation with added methanol was carriedout.

About 38 parts by weight of a feather-light lactulose v was difficultysoluble in absolute methanol. If desired, therefore, anotherrecrystallization can be carried out preferably using to percentmethanol.

The separation of the calcium can also be carried out with ionexchangers.

What is claimed is:

1. Calcium lactulosate prepared by introducing into a dilute aqueoussolution of a crude lactulose syrup about 0.7 to 4 parts by weight ofcalcium oxide per part by weight of lactulose in the crude syrup at atempera ture of about 0 to 15 C., allowing the resultant mixture tostand under conditions permitting maintenance of the temperature toabout 0 to 15 C., and separating off the calcium lactulosate therebyformed.

